Active specific immunotherapy was investigated in two experimental models using the methylcholanthrene-induced fibrosarcomas of C3H/HeJ mice. The first study investigated the efficacy of antigen specific therapy of postsurgical metastases using an artificial metastasis model; the second established the more clinically relevant spontaneous model for investigation of antigen-specific immunotherapy. Administration of tumor-specific transplantation antigens (TSTA) extracted from viable MCA-F cells using 2.5% n-butanol solution to mice augmented immunity of the primary MCA-F tumor. Two weeks after the footpad inoculation of 2 x 10[unreadable]5[unreadable] MCA-F cells, tumor-bearing limbs were amputated and the mice challenged intravenously with 5 x 10[unreadable]4[unreadable] clone 9-4 cells. Treatment with either 50 micrograms TSTA subcutaneously or 20 mg/kg cyclophosphamide intraperitoneally failed to retard tumor colonization in the lung, yet combination therapy reduced the incidence of colonization by 70% compared with surgery alone, and by 56% compared with surgery and cyclophosphamide. The combined effects of TSTA and cyclophosphamide were immunologically specific: combined therapy with MCA-D TSTA did not afford protection against intravenous challenge with the MCA-F clone 94. The TSTA-induced specific immune mechanisms are probably T-cell mediated, while simultaneous treatment with cyclophosphamide inhibits suppressor cell function. In seeking a model, spontaneously metastasizing variants were obtained from three antigenically different MCA-induced neoplasms (MCA-F, MCA-D, MCA-2A). Postsurgical spontaneous metastasis to the lung depended upon the size of the primary tumor and the duration of the neoplastic disease. The presence of the primary tumor retarded lung colonization in both the artificial and spontaneous models. Artificial metastases induced by intravenous challenge with clone 9-4 cells, in the presence or absence of a subcutaneous implant of the nonmetastatic MCA-F concomitant immunity, was greater in 2 cm tumor burdens than in mice bearing 0.6 cm tumors (p less than 0.005). Sinecomitant inhibition of metastasis was significantly greater in mice bearing 7-\or 14-day neoplasms, but not after resection of large tumors (p less than 0.001 and p less than 0.05). Intravenous challenge of mice bearing antigenically different tumors with variant cells revealed that in small tumor burdens concomitant immunity was specific, while in large tumor burdens it was nonspecific. There are two mechanisms for the suppression of metastatic outgrowth: (1) specific immunity probably induced by TSTA, and (2) nonspecific resistance possibly mediated by the immune system. (TT)